ABSTRACT Characterizing the molecular mechanisms that underlie alcohol-induced liver injury and the risk of hepatocellular carcinoma (HCC) is immensely valuable for the study of alcoholic liver diseases (ALDs). We demonstrated, for the first time, that alcohol increases Brf1 (TFIIIB-related factor 1) expression and Pol III gene (RNA polymerase III-dependent gene) transcription in cell culture models. This induction occurs as well in alcohol-fed wild type (WT) mice. Increased Brf1 expression and Pol III gene transcription promote liver tumor formation in alcohol-fed NS5A (HCV non-structural 5A protein) transgenic mice, but not in control diet-fed NS5A mice. Our preliminary studies have revealed that Brf1 is highly expressed in human HCC cases. High expression of Brf1 in human HCC displays a short survival time. Further analysis indicates that Brf1 and Pol III gene transcription are enhanced in the cases of Alcohol-drinker HCC. Our recent studies have indicated that alcohol activates MSK1 (mitogen- and stress-activated protein kinase 1), which mediates cell transformation and tumor formation in other cancer models. Given this compelling evidence, we propose a hypothesis that ethanol activates JNK1, which mediates MSK1 activity to modulates Brf1 expression and Pol III gene transcription, thereby contributing to alcoholic liver disease and liver tumor development. Using cell culture models and animal models, we will determine the roles of MSK1 and Brf1 as crucial factors in the alcohol-induced response. These studies will allow us to explore the molecular mechanism of alcohol- associated liver diseases and HCC. The following aims will be explored: AIM 1. TO TEST SIGNALING EVENTS OF ALCOHOL-INDUCED DEREGULATION OF POL III GENES; AIM 2. TO DETERMINE HOW ALCOHOL-INDUCED BRF1 EXPRESSION IS MODULATED; AIM 3. TO TEST IF BRF1 REDUCTION REPRESSES ALCOHOL-PROMOTED LIVER TUMOR FORMATION. Successful completion of these proposed aims should greatly enhance our understanding of molecular mechanism of alcohol-associated liver cancer. The inhibition of Brf1 and Pol III gene expression by using MSK1 KO mice and tamoxifen inducible conditional Brf1 KO mice should result in a repression of liver tumor formation. Therefore, the results from the proposed project could provide a potential strategy for the treatment of liver cancer.